Though most people have used potentially addicting substances such as nicotine and alcohol, only a minority of the population becomes addicted. Evidence from family, twin and adoption studies strongly suggests that there is a common genetic predisposition for dependence across multiple substances and recent studies have begun to identify specific genes associated with addiction. This proposal is a candidate gene association study of extreme phenotypes using data and genetic material collected in the NIDA funded genetic epidemiology project "A Family Study of Cocaine Dependence." This study conducted extensive interviews on cocaine dependent cases and non-dependent community based controls, and blood samples were collected for future genetic analysis. Cases are individuals who were identified in chemical dependency treatment settings with cocaine dependence and 93 percent exhibited poly-substance dependence. The control group consists community-based subjects who have never exhibited dependence on any substance. Candidate genes will be targeted for genotyping using state of the art technology. The aims of this study are: Aim 1: To examine candidate genes in polysubstance dependent cases and non-dependent controls. Genotyping of 1536 SNPs across candidate genes will be completed through the Center for Inherited Disease Research (CIDR). Aim 2: To follow up significant associations with additional genotyping to further characterize associations with polysubstance dependence. Additionally, in years 2 and 3 of the project, the study will pursue the examination and testing of genes identified by other investigators. The following aims are exploratory in nature and will allow further generation of hypotheses- Aim 3: To examine the influence of ethnicity, gender, comorbidity, and other novel phenotypes with the "at risk" alleles, genotypes, and haplotypes after significant associations are determined. Aim 4: To examine complex genetics of substance dependence and quantitative phenotypes using additional genetic analyses of gene-gene and gene-environment interaction This project uses a multidisciplinary approach, bringing together expertise in many domains to study the complex problem of addiction. Data from this proposal will be become part of the NIDA Genetics Consortium to be made available to the scientific community.